tbuckley/cabot-search huggingface dataset:
Analysis of MRE11 and Mortality Among Adults With Muscle-Invasive Bladder Cancer Managed With Trimodality Therapy
Authors: Anthony M. Magliocco, Jennifer Moughan, David T. Miyamoto, Jeff Simko, William U. Shipley, Phillip J. Gray, Michael P. Hagan, Matthew Parliament, William J. Tester, Anthony L. Zietman, Susan McCarthy, Daryoush Saeed-Vafa, Yin Xiong, Taylor Ayral, Alan C. Hartford, Ashish Patel, Seth A. Rosenthal, Susan Chafe, Richard Greenberg, Michael A. Schwartz, Mark E. Augspurger, John A. Keech, Kathryn A. Winter, Felix Y. Feng, Jason A. Efstathiou
Journal: JAMA Network Open (2022)

Importance Bladder-preserving trimodality therapy can be an effective alternative to radical cystectomy for treatment of muscle-invasive bladder cancer (MIBC), but biomarkers are needed to guide optimal patient selection. The DNA repair protein MRE11 is a candidate response biomarker that has not been validated in prospective cohorts using standardized measurement approaches. Objective To evaluate MRE11 expression as a prognostic biomarker in MIBC patients receiving trimodality therapy using automated quantitative image analysis. Design, Setting, and Participants This prognostic study analyzed patients with MIBC pooled from 6 prospective phase I/II, II, or III trials of trimodality therapy (Radiation Therapy Oncology Group [RTOG] 8802, 8903, 9506, 9706, 9906, and 0233) across 37 participating institutions in North America from 1988 to 2007. Eligible patients had nonmetastatic MIBC and were enrolled in 1 of the 6 trimodality therapy clinical trials. Analyses were completed August 2020. Exposures Trimodality therapy with transurethral bladder tumor resection and cisplatin-based chemoradiation therapy. Main Outcomes and Measures MRE11 expression and association with disease-specific (bladder cancer) mortality (DSM), defined as death from bladder cancer. Pretreatment tumor tissues were processed for immunofluorescence with anti-MRE11 antibody and analyzed using automated quantitative image analysis to calculate a normalized score for MRE11 based on nuclear-to-cytoplasmic (NC) signal ratio. Results Of 465 patients from 6 trials, 168 patients had available tissue, of which 135 were analyzable for MRE11 expression (median age of 65 years [minimum-maximum, 34-90 years]; 111 [82.2%] men). Median (minimum-maximum) follow-up for alive patients was 5.0 (0.6-11.7) years. Median (Q1-Q3) MRE11 NC signal ratio was 2.41 (1.49-3.34). Patients with an MRE11 NC ratio above 1.49 (ie, above first quartile) had a significantly lower DSM (HR, 0.50; 95% CI, 0.26-0.93; P = .03). The 4-year DSM was 41.0% (95% CI, 23.2%-58.0%) for patients with an MRE11 NC signal ratio of 1.49 or lower vs 21.0% (95% CI, 13.4%-29.8%) for a ratio above 1.49. MRE11 NC signal ratio was not significantly associated with overall survival (HR, 0.84; 95% CI, 0.49-1.44). Conclusions and Relevance Higher MRE11 NC signal ratios were associated with better DSM after trimodality therapy. Lower MRE11 NC signal ratios identified a poor prognosis subgroup that may benefit from intensification of therapy.
A Water‐Soluble Quercetin Conjugate with Triple Targeting Exerts Neuron‐Protective Effect on Cerebral Ischemia by Mitophagy Activation (Adv. Healthcare Mater. 22/2022)
Authors: Juan Cen, Runfang Zhang, Tingkui Zhao, Xin Zhang, Chuan Zhang, Jie Cui, Keqing Zhao, Shaofeng Duan, Yuqi Guo
Journal: Advanced Healthcare Materials (2022)

Neuroprotection In the article 2200817 by Shaofeng Duan, Yuqi Guo, and co-workers, hyaluronic acid (HA)-based targeting delivery systems SS31-HA-Quercetin are synthesized with great water-solubility. This delivery system can penetrate the blood–brain barrier, enrich and release drugs at the site of ischemic injury, and finally enter the mitochondria to achieve tertiary targeted drug delivery, thus effectively protecting ischemic neurons by modulating reactive oxygen species to activate HIF-1α/TFEB-mediated mitochondrial autophagy.
Analysis of COVID-19 Vaccination Status Among Parents of Hospitalized Children Younger Than 5 Years With SARS-CoV-2 Infection During the Delta and Omicron Waves
Authors: Florie Solignac, Naïm Ouldali, Camille Aupiais, Paul Casha, Robert Cohen, Corinne Levy, François Angoulvant
Journal: JAMA Network Open (2022)

This cohort study uses COVID-19 Pediatric Observatory study data to analyze the vaccination status of parents with young children hospitalized for SARS-CoV-2 variants Delta and Omicron.
Microtissue‐Based Bioink as a Chondrocyte Microshelter for DLP Bioprinting (Adv. Healthcare Mater. 22/2022)
Authors: Xinfang Xie, Shuang Wu, Shan Mou, Nengqiang Guo, Zhenxing Wang, Jiaming Sun
Journal: Advanced Healthcare Materials (2022)

Digital Light Processing Bioprinting In article 2201877, Zhenxing Wang, Jiaming Sun, and co-workers introduce a novel microtissue bioink prepared by crosslinking acellular matrix microparticles and GelMA hydrogel with a specific proportion. For instance, a digital light processing (DLP)-bioprinted ear is created using microtia chondrocytes microtissue bioink. The microtissue composite bioink for DLP printing not only enables accurate assembly of organ building blocks but also provides a 3D shelter to ensure printed cells' viability.
FDG-PET Positivity and Overall Survival in Renal Cell Carcinoma
Authors: Justin Ferdinandus, Ines Maríc, Christopher Darr, Claudia Kesch, Timo Bartel, Wolfgang Peter Fendler, Viktor Grünwald
Journal: JAMA Network Open (2022)

This cohort study examines positron emission tomography in renal cell carcinoma and its association with overall survival among adults.
Characterization of Oncology Clinical Trials Using Germline Genetic Data
Authors: Ashwin V. Kammula, Alejandro A. Schäffer, Padma Sheila Rajagopal
Journal: JAMA Network Open (2022)

Importance The recent successes of poly-ADP ribose polymerase (PARP) inhibitors and belzutifan support germline genetic data as an exciting, accessible source for biomarkers in cancer treatment. This study hypothesizes, however, that most oncology clinical trials using germline data largely prioritize BRCA1/2 as biomarkers and PARP inhibitors as therapy. Objective To characterize past and ongoing oncology trials that use germline data. Design, Setting, and Participants This retrospective cross-sectional study of oncology trials used the Informa Trialtrove database to evaluate trial attributes. Trials using germline information (including the terms germline , hereditary , or inherited in the title, treatment plan, interventions, end points, objectives, results, or notes) and conducted globally between December 1, 1990, and April 4, 2022 (data freeze date), were included. Main Outcomes and Measures Trials by cancer type, phase, participants, sponsor type, end points, outcomes, and locations were described. Associated biomarkers and mechanisms of action for studied therapeutic interventions were counted. How germline data in trial inclusion and exclusion criteria are associated with end points, outcomes, and enrollment were also examined. Results A total of 887 of 84 297 (1.1%) oncology clinical trials in the Trialtrove database that use germline data were identified. Most trials were conducted in cancer types where PARP inhibitors are already approved. A total of 74.8% (672) of trials were performed in the phase 2 setting or above. Trials were primarily sponsored by industry (523 trials [59.0%]), academia (382 trials [43.1%]), and the government (274 trials [30.9%]), where trials may have multiple sponsor types. Among 343 trials using germline data with outcomes in Trialtrove, 180 (52.5%) reported meeting primary end points. Although BRCA1/2 are the most frequent biomarkers seen ( BRCA1 , 224 trials [25.3%]; BRCA2 , 228 trials [25.7%]), trials also examine pharmacogenomic variants and germline mediators of somatic biomarkers. PARP inhibitors or immunotherapy were tested in 69.9% of trials; PARP inhibition was the most frequently studied mechanism (367 trials [41.4%]). An overwhelming number of trials using germline data were conducted in the US, Canada, and Europe vs other countries, mirroring disparities in cancer genetics data. Germline data in inclusion and exclusion criteria are associated with altered end point, outcomes, and enrollment compared with oncology trials with no germline data use. Examples of inclusion and exclusion criteria regarding germline data that may unintentionally exclude patients were identified. Conclusions and Relevance These findings suggest that for germline biomarkers to gain clinical relevance, trials must expand biomarkers, therapies, and populations under study.
A phase 2 study of interleukin-22 and systemic corticosteroids as initial treatment for acute GVHD of the lower GI tract
Authors: Doris M. Ponce, Amin M. Alousi, Ryotaro Nakamura, John Slingerland, Marco Calafiore, Karamjeet S. Sandhu, Juliet N. Barker, Sean Devlin, Jinru Shia, Sergio Giralt, Miguel-Angel Perales, Gillian Moore, Samira Fatmi, Cristina Soto, Antonio Gomes, Paul Giardina, LeeAnn Marcello, Xiaoqiang Yan, Tom Tang, Kevin Dreyer, Jianmin Chen, William L. Daley, Jonathan U. Peled, Marcel R. M. van den Brink, Alan M. Hanash
Journal: Blood (2022)
High frequency of low-count monoclonal B-cell lymphocytosis in hospitalized COVID-19 patients
Authors: Guillermo Oliva-Ariza, Blanca Fuentes-Herrero, Cristina Carbonell, Quentin Lecrevisse, Alba Pérez-Pons, Alba Torres-Valle, Julio Pozo, José Ángel Martín-Oterino, Óscar González-López, Amparo López-Bernús, Marta Bernal-Ribes, Moncef Belhassen-García, Oihane Pérez-Escurza, Martín Pérez-Andrés, Lourdes Vazquez, Guillermo Hernández-Pérez, Francisco Javier García Palomo, Pilar Leoz, Pilar Costa-Alba, Elena Pérez-Losada, Ana Yeguas, Miryam Santos Sánchez, Marta García-Blázquez, Francisco Javier Morán-Plata, Daniela Damasceno, Vitor Botafogo, Noemí Muñoz-García, Rafael Fluxa, Teresa Contreras-Sanfeliciano, Julia Almeida, Miguel Marcos, Alberto Orfao
Journal: Blood (2022)
Epinephrine before defibrillation in patients with shockable in-hospital cardiac arrest: propensity matched analysis
Authors: Saket Girotra
Journal: BMJ (2022)

Epinephrine before defibrillation in patients with shockable in-hospital cardiac arrest: propensity matched analysisIn this paper by Evans and colleagues (BMJ 2021;375:e066534, doi:, published
Using Rapid Randomized Trials to Improve Health Care Systems
Authors: Leora I. Horwitz, Holly A. Krelle
Journal: Annual Review of Public Health (2022)

Rapid randomized controlled trials have been surprisingly rare in health care quality improvement (QI) and systems interventions. Applying clinical trials methodology QI work brings two distinct fields together, applying the robustness of randomized controlled trials (RCTs) to the practical, operational learnings of the well-established QI field. Rapid trials also add a third element-speed-that enables health care systems to rapidly test multiple variations of an intervention in much the same way that A/B testing is done in the technology sector. When performed well, these rapid trials free researchers and health care systems from the requirement to be correct the first time (because it is low cost and quick to try something else) while offering a standard of evidence often absent in QI. Here we outline the historical underpinnings of this approach, provide guidance about how best to implement it, and describe lessons learned from running more than 20 randomized projects in the NYU Langone Health system.
Positive- and Negative-Pressure Ventilation Characterized by Local and Global Pulmonary Mechanics
Authors: Shoujin Dong, Wenting Lu, Yongsheng Wang
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

"Positive- and Negative-Pressure Ventilation Characterized by Local and Global Pulmonary Mechanics." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp. –
COVID-19 and Excess All-Cause Mortality in the US and 20 Comparison Countries, June 2021-March 2022
Authors: Alyssa Bilinski, Kathryn Thompson, Ezekiel Emanuel
Journal: JAMA (2022)

This study compares the COVID-19 per capita overall and excess mortality rates in the US vs rates for 20 Organization for Economic Co-operation and Development countries and the timing of any increases in excess mortality between June 2021 and December 2021 (Delta) and December 2021 to March 2022 (Omicron).
Pest sensitization to cockroach, mouse, and rat: An Italian multicenter study
Authors: Gennaro Liccardi, Maria Beatrice Bilò, Luigino Calzetta, Manlio Milanese, Matteo Martini, Megon Bresciani, Marcello Cilia, Francesco Cucinelli, Romina D'Angelo, Annamaria Feliziani, Francesca Larese Filon, Rocco Longo, Laura Losappio, Giusy Manzotti, Paola Minale, Stella Modica, Francesco Murzilli, Antonino Musarra, Giuseppe Pingitore, Battista Roberto Polillo, Francesca Puggioni, Oliviero Quercia, Carla Rapone, Paola Rogliani
Journal: Allergy (2022)

Appendix S1 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Covid-19: NICE rejects five treatments over uncertain evidence and price in draft guidance
Authors: Elisabeth Mahase
Journal: BMJ (2022)

Covid-19: NICE rejects five treatments over uncertain evidence and price in draft guidanceElisabeth Mahase NICE has recommended three drugs-nirmatrelvir plus ritonavir (Paxlovid), tocilizumab (RoActemra), and baricitinib (Olumiant)-for the treatment of covid-19 in adults, as part of draft guidance. 11
Ciliogenesis is intrinsically altered in COPD small airways
Authors: Emilie Luczka-Majérus, Arnaud Bonnomet, Adeline Germain, Nathalie Lalun, Claire Kileztky, Jeanne-Marie Perotin, Gaëtan Deslée, Gonzague Delepine, Myriam Polette, Valérian Dormoy, Christelle Coraux
Journal: European Respiratory Journal (2022)

<b>An alteration of primary and motile ciliogenesis is detected in mild/moderate COPD small airways and could be at the origin of the initiation of epithelial remodelling</b>http://bit.ly/3Tz3JDj
Airway inflammation and hyperresponsiveness in subjects with respiratory symptoms and normal spirometry
Authors: Louis-Philippe Boulet, Marie-Ève Boulay, Andréanne Côté, J. Mark FitzGerald, Céline Bergeron, Catherine Lemière, M. Diane Lougheed, Katherine L. Vandemheen, Shawn D. Aaron
Journal: European Respiratory Journal (2022)

Background Subjects without a previous history of asthma, presenting with unexplained respiratory symptoms and normal spirometry, may exhibit airway hyperresponsiveness (AHR) in association with underlying eosinophilic (type 2 (T2)) inflammation, consistent with undiagnosed asthma. However, the prevalence of undiagnosed asthma in these subjects is unknown. Methods In this observational study, inhaled corticosteroid-naïve adults without previously diagnosed lung disease reporting current respiratory symptoms and showing normal pre- and post-bronchodilator spirometry underwent fractional exhaled nitric oxide ( F ENO ) measurement, methacholine challenge testing and induced sputum analysis. AHR was defined as a provocative concentration of methacholine causing a 20% fall in forced expiratory volume in 1 s (PC 20 ) &lt;16 mg·mL −1 and T2 inflammation was defined as sputum eosinophils &gt;2% and/or F ENO &gt;25 ppb. Results Out of 132 subjects (mean± sd age 57.6±14.2 years, 52% female), 47 (36% (95% CI 28–44%)) showed AHR: 20/132 (15% (95% CI 9–21%)) with PC 20 &lt;4 mg·mL −1 and 27/132 (21% (95% CI 14–28%)) with PC 20 4–15.9 mg·mL −1 . Of 130 participants for whom sputum eosinophils, F ENO or both results were obtained, 45 (35% (95% CI 27–43%)) had T2 inflammation. 14 participants (11% (95% CI 6–16%)) had sputum eosinophils &gt;2% and PC 20 ≥16 mg·mL −1 , suggesting eosinophilic bronchitis. The prevalence of T2 inflammation was significantly higher in subjects with PC 20 &lt;4 mg·mL −1 (12/20 (60%)) than in those with PC 20 4–15.9 mg·mL −1 (8/27 (30%)) or ≥16 mg·mL −1 (25/85 (29%)) (p=0.01). Conclusions Asthma, underlying T2 airway inflammation and eosinophilic bronchitis may remain undiagnosed in a high proportion of symptomatic subjects in the community who have normal pre- and post-bronchodilator spirometry.
Kruppel-like factor 1–GATA1 fusion protein improves the sickle cell disease phenotype in mice both in vitro and in vivo
Authors: Jianqiong Zhu, Hongzhen Li, Wulin Aerbajinai, Chutima Kumkhaek, Mehdi Pirooznia, Ankit Saxena, Pradeep Dagur, Kyung Chin, Griffin P. Rodgers
Journal: Blood (2022)

Sickle cell disease (SCD) and β-thalassemia are among the most common genetic disorders worldwide, affecting global health and mortality. Hemoglobin A2 (HbA2, α2δ2) is expressed at a low level in adult blood due to the lack of the Kruppel-like factor 1 (KLF1) binding motif in the δ-globin promoter region. However, HbA2 is fully functional as an oxygen transporter, and could be a valid antisickling agent in SCD, as well as a substitute for hemoglobin A in β-thalassemia. We have previously demonstrated that KLF1-GATA1 fusion protein could interact with the δ-globin promoter and increase δ-globin expression in human primary CD34+ cells. We report the effects of 2 KLF1-GATA1 fusion proteins on hemoglobin expression, as well as SCD phenotypic correction in vitro and in vivo. Forced expression of KLF1-GATA1 fusion protein enhanced δ-globin gene and HbA2 expression, as well as reduced hypoxia-related sickling, in erythroid cells cultured from both human sickle CD34+ cells and SCD mouse hematopoietic stem cells (HSCs). The fusion proteins had no impact on erythroid cell differentiation, proliferation, and enucleation. Transplantation of highly purified SCD mouse HSCs expressing KLF1-GATA1 fusion protein into SCD mice lessened the severity of the anemia, reduced the sickling of red blood cells, improved SCD-related pathological alterations in spleen, kidney, and liver, and restored urine-concentrating ability in recipient mice. Taken together, these results indicate that the use of KLF1-GATA1 fusion constructs may represent a new gene therapy approach for hemoglobinopathies.
Cancer-Associated Fibroblasts in Inflammation and Antitumor Immunity
Authors: Kilian B. Kennel, Müge Bozlar, Adalbert F. De Valk, Florian R. Greten
Journal: Clinical Cancer Research (2022)

Abstract Tumor-associated inflammation (TAI) is a feature of essentially all cancers and can confer both tumor-promoting and -suppressive functions. Cancer-associated fibroblasts (CAF) comprise one very heterogeneous cellular component of the tumor microenvironment characterized by a high degree of plasticity. Recent single-cell sequencing analyses revealed distinct CAF populations in various human cancers and helped to define key CAF subtypes, such as myofibroblastic, inflammatory, and antigen-presenting CAFs, with the first two being present in virtually all tumors. Importantly, these three CAF populations are involved in and modulate the positive and negative consequences of TAI. The remarkable plasticity of CAFs allows them to shift phenotypically and functionally in response to environmental changes. In this review, we describe how CAFs nurture tumor-promoting inflammation and suppress adaptive immunity. We also summarize the recently emerging evidence pertaining to tumor-suppressive CAF functions in the context of TAI. Finally, we summarize therapeutic concepts that aim at modulating CAF functions or depleting immunosuppressive CAFs to synergize with immunotherapy.
Astrocytes mediate long-lasting synaptic regulation of ventral tegmental area dopamine neurons
Authors: Linda Maria Requie, Marta Gómez-Gonzalo, Michele Speggiorin, Francesca Managò, Marcello Melone, Mauro Congiu, Angela Chiavegato, Annamaria Lia, Micaela Zonta, Gabriele Losi, Vanessa Jorge Henriques, Arianna Pugliese, Giada Pacinelli, Giovanni Marsicano, Francesco Papaleo, Anna Lisa Muntoni, Fiorenzo Conti, Giorgio Carmignoto
Journal: Nature Neuroscience (2022)
Transcriptional Antagonism by CDK8 Inhibition Improves Therapeutic Efficacy of MEK Inhibitors
Authors: Clare F. Malone, Minjee Kim, Gabriela Alexe, Kathleen Engel, Alexandra B. Forman, Amanda Robichaud, Amy Saur Conway, Amy Goodale, Ashleigh Meyer, Delan Khalid, Allen Thayakumar, John M. Hatcher, Nathanael S. Gray, Federica Piccioni, Kimberly Stegmaier
Journal: Cancer Research (2022)

Abstract Aberrant RAS/MAPK signaling is a common driver of oncogenesis that can be therapeutically targeted with clinically approved MEK inhibitors. Disease progression on single-agent MEK inhibitors is common, however, and combination therapies are typically required to achieve significant clinical benefit in advanced cancers. Here we focused on identifying MEK inhibitor-based combination therapies in neuroblastoma with mutations that activate the RAS/MAPK signaling pathway, which are rare at diagnosis but frequent in relapsed neuroblastoma. A genome-scale CRISPR-Cas9 functional genomic screen was deployed to identify genes that when knocked out sensitize RAS-mutant neuroblastoma to MEK inhibition. Loss of either CCNC or CDK8, two members of the mediator kinase module, sensitized neuroblastoma to MEK inhibition. Furthermore, small-molecule kinase inhibitors of CDK8 improved response to MEK inhibitors in vitro and in vivo in RAS-mutant neuroblastoma and other adult solid tumors. Transcriptional profiling revealed that loss of CDK8 or CCNC antagonized the transcriptional signature induced by MEK inhibition. When combined, loss of CDK8 or CCNC prevented the compensatory upregulation of progrowth gene expression induced by MEK inhibition. These findings propose a new therapeutic combination for RAS-mutant neuroblastoma and may have clinical relevance for other RAS-driven malignancies. Significance: Transcriptional adaptation to MEK inhibition is mediated by CDK8 and can be blocked by the addition of CDK8 inhibitors to improve response to MEK inhibitors in RAS-mutant neuroblastoma, a clinically challenging disease.
An ECM‐Mimicking, Injectable, Viscoelastic Hydrogel for Treatment of Brain Lesions
Authors: Yan Hu, Yuanbo Jia, Siwei Wang, Yufei Ma, Guoyou Huang, Tan Ding, Dayun Feng, Guy M. Genin, Zhao Wei, Feng Xu
Journal: Advanced Healthcare Materials (2022)

Brain lesions can arise from traumatic brain injury, infection, and craniotomy. Although injectable hydrogels show promise for promoting healing of lesions and health of surrounding tissue, enabling cellular ingrowth and restoring neural tissue continue to be challenging. It is hypothesized that these challenges arise in part from the mismatch of composition, stiffness, and viscoelasticity between the hydrogel and the brain parenchyma, and this hypothesis is tested by developing and evaluating a self-healing hydrogel that not only mimics the composition, but also the stiffness and viscoelasticity of native brain parenchyma. The hydrogel is crosslinked by dynamic boronate ester bonds between phenylboronic acid grafted hyaluronic acid (HA-PBA) and dopamine grafted gelatin (Gel-Dopa). This HA-PBA/Gel-Dopa hydrogel could be injected into a lesion cavity in a shear-thinning manner with rapid hemostasis, high tissue adhesion, and efficient self-healing. In an in vivo mouse model of brain lesions, the multi-functional injectable hydrogel is found to support neural cell infiltration, decrease astrogliosis and glial scars, and close the lesions. The results suggest a role for extracellular matrix-mimicking viscoelasticity in brain lesion healing, and motivate additional experimentation in larger animals as the technology progresses toward potential application in humans.
Frequent presence of major dust mite allergens in human digestive tissues of children with gastritis
Authors: Ying Zhou, Shudong Yang, Qiong Lin, Qixin He, Yubao Cui
Journal: Allergy (2022)

Figure S1. Appendix S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.